1, 17-dioxygenated 5alpha-androstanes and delta analogs



Paul D. Klimstra, Northbrook, Ill.,

United States Patent 3,257,428 1,17-DIOXYGENATED Szx-ANDRGSTANES AND A ANALOGS assignor to G. D. Searle & Co., Chicago, 111., a corporation of Delaware N Drawing. Filed July 10, 1962, Ser. No. 208,954 9 Claims. (Cl. 260- 397.4)

. This invention relates to l,17-dioxygenated Set-androstanes and A steroids otherwise identical, and also to processes for the preparation thereof. More particularly,

this invention provides new and useful.v chemical com- 2 pounds of the formula From 175 acetoxy 10:,206 epoxy-a -androstan-3- one, on heating with hydrazine hydrate, is obtained 50:-

androst 2 ene 1u,l7[3 diol which, after approximately 2 hours at roomtem-peratures in the presence of pyridine and alkanoic acid anhydride, affords the corresponding 17-alkanoate ester. The corresponding diester instead of the monoester preponderates if contact is prolonged to 12 or more hours. Acetonic chromic acid oxidation of 51x androst 2 ene :,1713 diol gives 5a-androst-2- ene-1,17-di0ne which, in turn, is reduced to the 2,3-dihydro derivative by hydrogenation over RuO Preparation of 17/3 hydroxy 5a androst 2 en 1- one'proceeds, seriatim, by protection of the hydroxyl in 175 hydroxy 5 a androst 1 en 3 one via formation ofthe pyranyl ether, epoxidation of the double bond with hydrogen peroxide, conversion of the epoxide to the 1ahydroxy-Z-ene derivative'with hydrazine hydrate, acetonic dotted line in ring A denotes optional A unsaturation;

alternatively, Z represents a grouping of the formula alkyl I in which R represents an optionally-esterified hydroxy].

neopentyl, hexyl, 'isohexyl, heptyl, octyl, and like .'C,,H groupings wherein 'n represents a positive integer less than 9. Among the esterifying moieties"contemplated by Z, Z", and R, residues of alkanoic acids are preferred, especially lower alkanoyl radicals, i.e.,

groupings of the formula 7 lower alkylCO- lower alkyl being defined as above.

The compounds to which this inventionrelates are useful because of their valuable pharmacological properties. Thus, for example,-the compounds are anabolic, androgenic, progestational, and adapted to inhibit the effects of estrogen on the uterus; moreover, being antibacterial, they retard or prevent the growth of Diplococcus pneumoniae.

The 17u-(lower alkyl)-5a-androst-2-ene-1a,17B-diols hereof are prepared by heating the corresponding lu,2aepoxy 175 hydroxy 17ot-(10W61 alkyl)-5a-androstan- 3-ones with hydrazine hydrate, and are monoesterified at carbon atom No. 1 by contacting with pyridine and alkanoic acid anhydride at room temperatures for upwards of 12 hours. Diesterification results if contact is at reflux rather than room temperatures for several hours. From the diesters thus obtained, on warming briefly with aqueous methanolic sodium carbonate, the 17-monoesters result. Oxidation of the 17d-(lower aIkyD-Sa-androSt- 2-ene-la,l7/3-diols with Jones reagent (a standardized preparation of CrO described at J. Chem. Soc., 1946, 39) in acetonic medium affords the corresponding l-ones, whereas hydrogenation catalyzed by ruthenium dioxide yields the corresponding 2,3-dihydro derivatives. The latter compounds are selectively esterified by the same techniques which apply to their A progenitors, and likewise alford the corresponding l-ones on acetonic chromic acid oxidation.

chromic acid oxidation of the l-hydroxyl to a keto group, and cleavage of the pyranyl ether linkage with methanolic p-toluenesulfonic acid in acetone. The double bond in 176 hydroxy 5m androst 2 en l one is, of course, subject to reduction by ruthenium dioxide-catalyzed hydrogenation.

The lot alkanoyloxy 50c androst 2 en 175 01s hereof eventuate upon esterification of l7fl-pyranyloxy- 50c androst 2 en 1a 01 with pyridine and alkanoic acid anhydride at room temperatures for 12 or more hours,

' followed by heating with p-toluenesulfonic acid. These, in turn, afford the corresponding 17-ones via acetonic Jones'reagent; and the l-ester group is saponifiable by warming in aqueous methanolic sodium. carbonate. Alternatively, ethynylation of a 1a-alkanOyl-Sa-androst-Z-en- -17-one at temperatures of theorder of 60 in alkaline ethereal solvent medium yields l7a-ethynyl-5d-androst-2- ene-1a,17}8-diol, which can be selectively esterified by the .same techniques which apply to the l7-alkyl diols of this invention or oxidized to the l-one with acetonic chromic acid. Likewise, the ethynylation, selective esterification, and oxidation procedures aforesaid provide the corresponding 2,3-dihydro compounds via preliminary reduction of the double bondin the la-alkanoyl-Sa-androst-Z- en-l7-one starting material. i

The following examples describe in detail compounds illustrative of the present invention and methods which have been devised for their preparation. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of this disclosure. Throughout the examples hereinafter set forth, temperatures are given in. degrees centigrade C.) and relative amounts of materials in parts by Weight, except as otherwise noted. Specific rotation is referred to the D line of sodium.

EXAMPLE 1 17a methyI-Sa-andr st-Z-ene-Iu,17/8-diol.A mixture of 8 parts of 1aim-epoxy 17/3-hydroxy-l7u-n1ethyl-5aandrostan-B-one and approximately 124 parts of 100% hydrazine hydrate is allowed to stand /2 hour at room temperatures, is then heated at 100 for 15 minutes,

and is finally heated at under reflux for 15 minutes.

The product thus isolated C H Hz 0 E EXAMPLE 2 1oz acetoxy-J 7a-methyl-5m-andr0st-2-en-17,8-0l.A solution of 3 parts of 17a-methyl-Sa-androst-Z-ene-1a,l7{3- diol in a mixture of 44 parts of dry pyridine and 22 parts of acetic anhydride is allowed to stand at room temperatures overnight, then poured into 300 parts of water. The gum which forms is extracted into ether. The ether extract is consecutively washed with water, 5% hydrochloric acid, and aqueous 5% sodium bicarbonate, whereupon it is dried over anhydrous potassium carbonate in the presence of decolorizing charcoal, filtered, and stripped of solvent by vacuum distillation. The residual oil is crystallized from aqueous methanol. The product thus isolated is lu-acetoxy-l7a-methyl-5a-androst-2-en- 175-01 melting at 6l.5-64, and having the formula orr ooo EXAMPLE 3 1a,]7,8-diacetoxy-17u-methyl-5a-andr0st-2-ene.A solution of 5 parts of 17a-methyl-5a-androst-2-ene-lot,l7,8- diol in a mixture of 70 parts of dry pyridine and 35 parts of acetic anhydride is heated at the boiling point in an atmosphere of nitrogen under reflux for 7 hours, then cooled and poured into 3 volumes of water. The precipitate which forms is filtered off, washed with water, and dried in air. The resultant material is taken up in ether; and the ether solution is dried over anhydrous potassium carbonate in the presence of decolorizing charcoal, th'en filtered andstripped of solvent by distillation. The residue is recrystallized from aqueous methanol to give la,

17/5 diacetoxy 17a-methyl-5a-androst 2-ene which, in chloroform solution, is characterized by infrared peaks at 3.4, 5:76, 6.01, and 7.95 microns. The product has the formula ooooH OHQCO o EXAMPLE 4 17B acetoxy-I7a-methyl-Sa-androst-Z-en-la-oL-To a solution of 20 parts of 1a,17/3-diacetoxy-l7a-methyl-5aandrost-Z-ene in 400 parts of methanol is added a solution of 7 parts of sodium carbonate in 80 parts of water. The resultant mixture is heated at approximately 45 with agitation for 15 minutes, whereupon it is chilled to 5 and water added until precipitation occurs. The precipitate is filtered off, washed with water, dried in air, and recrystallized from aqueous ethanol to give 17,8-acetoxy-l7amthyl-50t-3.I1dlOSt2-Il-lot-O1, which is characterized, in chloroform solution, by infrared peaks at 2.75, 3.4, 5.75, 6.01, and 7.93 microns. The product has the formula CH CH 5 joooort EXAMPLE 5 CH3 CHa EXAMPLE 6 J 7a-methyI-Sa-androstane-I 0a,] 7,8-'dz'ol.-A solution of 5 parts of 17u-methyl-5a-androst-2-ene-1a,17,8-diol in 160 parts of anhydrous ethanol is hydrogenated under 68 atmospheres pressure at in the presence of 2 parts of ruthenium dioxide for 18 hours. The resultant mixture is poured into 5 volumes of aqueous 2% sodium carbonate; and the precipitate thrown down is filtered off, washed with water, and dried in air. It is then taken up in ether, the ether solution is filtered, and the filtrate is freed of solvent by distillation. The residue, recrystallized from a mixture of acetone and hexane, affords 17amethyl-5a-androstane-la,17,B-diol melting at 191-193. The product has the formula EXAMPLE 7 EXAMPLE 8 17B hydroxy-Um meJhyZ-Sa-androstan-l-ne.-To a solution of 4 parts of 17a-methyl-5ot-androstane-lu,175- diol in 160 parts of acetone is added a slight excess of Jones reagent. The excess is destroyed by introducing 1 part of 2-propanol, whereupon the inorganic salts thrown down are filtered oif and the filtrate poured into approximately volumes of water. The precipitate which forms is collected, Washed with Water, and recrystallized from aqueous methanol to afford 17,8-hydroXy-17amethyl-5ot-androstan-l-one melting at 173.5175. The product has the formula ornooo CH CH3 EXAMPLE 9 1 7,8-acetoxy-1 7ot-methyl-5u-andr0stan-1-0ne.--Substitution of 5 parts of 1713-hydroxy-l7oz-methyl-5et-androstanl-one for the l7tit-methyl-5at-androst-2-ene-1a,17fl-diol called for in Example '3 affords, by the procedure there detailed, 17,8-acetoxy-17a-methyl-5a-androstan-l-one, the formula of which is CH CH 5 V OCOCH t l j EXAMPLE 10 5 a-androst-Z-ene-I 0a,] 7fl-diol.A mixture of 2 parts of 17fl-acetoxy-1a,2w-epoxy5ot-androstan-3-one and approximately 31 parts of hydrazine hydrate is heated at 90 for 25 minutes, then at approximately 120 under reflux for minutes. The resultant mixture is cooled to around 5 whereupon the supernatant layer is decanted into Water. The aqueous mixture is extracted with ether, and the ether extract i dried over anhydrous potassium carbonate in the presence of decolorizing charcoal. Filtration, followed by distillation of solvent, leaves an oil which is partitioned between-methanol and ether. The ether phase is separated, washed with water, dried over anhydrous potassium carbonate, and stripped of solvent by distillation. The residual foam, recrystallized from a mixture of acetone and hexane, affords 5ot-androst-2-ene-la,17[i-diol melting at -143". The product has the formula EXAMPLE 11 17fl-acetoxy-5u-androst-Z-en-Iu-0l.A solution of 2 parts of 5a-androst-2-ene-lw,17fl-diol in a mixture of 30 parts of pyridine and 15 parts of acetic anhydride is maintained under nitrogen with agitation at room temperatures for 2 hours. It is thereupon poured into 300 parts of water, and the resultant mixture is extracted with ether. The ether extract is consecutively washed with 5% hydrochloric acid, aqueous 5% sodium bicarbonate, and water, then dried over-anhydrous potassium carbonate in the presence of decolorizing charcoal. Filtration and removal of solvent by distillation leaves an oil which, after further purification by chromatography on silica gel, using benzene and ethyl acetate as developing solvents, affords 17,8-acetoxy-5a-androst-Z-en-1a-ol. The product is characterized by infrared maxima at 2.75, 3.4, 5.77, 6.02, and 795 microns. It has the formula OCOCH EXAMPLE 12 1a,]7fl-diacetoxy-5 x-androst-2-ene.Substitution 0f 5 parts of 17fi-acetoxy-5wandrost-2-en-lot-o1 for the 17amethyl-5u-androst-2-ene-10:,17fl-di0l called for in Example 3 affords, by the procedure there detailed, 1a,17fl-diacetoxy-5a-androst-2-ene, the formula of which is OCOCH:

. EXAMPLE 13 Sa-andrOst-Z-ene-LI7-di0ne.A solution of 4 parts of SOL-HIICI'OSt-Z-fiIlC-l00,17fl dl01 and 64 parts of acetone is mixed with a slight excess of Jones reagent. The excess .is thereupon destroyed by the addition ,of 1 part of 2- propanol. Separation from the inorganic salts thrown down is effected by decanting the supernatant into 5 volumes of a mixture of ice and water. The resultant mixture is extracted With ether; and the, ether extract is washed with water, dried over anhydrous potassium carbonate in the presence of decolorizing charcoal, and filof ice and water.

tered. The filtrate is stripped of solvent by distillation, leaving an oil which is chromatographed on silica gel, using benzene and ethyl acetate as developing solvents. From an eluate comprising 5% ethyl acetate in benzene, upon evaporation of solvents, there is obtained a residue which, recrystallized from a mixture of acetone and hexane, affords Son-androst-Z-ene-1,17-dione melting at 151-154. The product has the formula OH; I

'EMMPLE 14 (A) 1 7 fl-pyrariyloxy-S a-androst-I -en-3-0ne .-A mixture of 1000 parts of 17B-hydroxy-5ot-androst-l-en-3-one, 1200 parts of dihydropyran, 10,000 parts of dichloromethane, and 1 part of p-toluenesulfonic acid monohydrate is allowed to stand at room temperatures overnight, whereupon it is washed thoroughly with water, dried over anhydrous potassium carbonate in the presence of decolorizing charcoal, filtered, and stripped of solvent by distillation. The residual dark oil is 17fi-pyranyloxy-5a-andr0st- 1-en-3-one.

(B) 1a,2u-ep0xy-1 713-pyrzmyloxy-5u-androstan-3-0ne.- To a solution of 20 parts of 17B-pyranyloxy-5wandrost- 1-en-3-one in approximately 272 parts of methanol at 5 is added a solution of 25 parts of 30% hydrogen peroxide in approximately 6 parts of methanolic 10% sodium hydroxide. The resultant mixture is allowed to stand for 20 minutes and then poured into 5 volumes of a mixture This mixture is extracted with dichloromethane and then with an ll-to-Z mixture of chloroform and methanol. The extracts are combined, washed with water, dried over anhydrous potassium carbonate in the presence of decolorizing charcoal, filtered, and stripped of solvent by distillation. The yellow oily residue solidifies on standing. Recrystallized from aqueous methanol, it melts at 123-125 This material is 1a,2u-epoxy-17,8- pyranyloxy-5a-andnoStan-3-one.

(C) 17B-pyranyl0xy-5a-aI drOst-Z-en-Ioz-0l.A mixture of 4 parts of 1aim-epoxy-17B-pyranyloxy-5a-androstan- 3-one and approximately 62 parts of 85% hydrazine hydrate is heated at 90100 for 5 minutes, then at 120 under reflux for 20 minutes. The resultant mixture is chilled, and the supernatant liquid is decanted and dis- I carded. The semi-solid residue is taken up in 40 parts of methanol, and the methanol solution is poured into 300 parts of cold water. The precipitate which forms is filtered 01f, washed with water, and dried in air. This material is 17/8-pyranyloxy-5a-androst-2-en-lot-o1.

(D) 17,9- pyranyl0xy-5a-andr0st-2-en-1-0ne.-A solution of 3 parts of 17/3-pyranyloxy-5a-androst-2-en-1a-ol in approximately 36 parts of acetone is mixed with a slight excess of Jones reagent. The excess reagent is thereupon destroyed with Z-propanol, i ollowing which the inorganic salts thrown down are filtered out and the filtrate poured into 350 parts of coldaqueous 1% sodium bicarbonate. The resultant mixture is extracted with ether; and the ether extract is washed with water, dried over anhydrous potassium carbonate in the presence of decolorizing charcoal, filtered, and stripped of solvent by distillation. The residual oil is 1713-pyrany1oxy-5u-androst-2-en-1-one.

(E) 17 3-hydrOxy-Sa-androst-Z-en-1-one.--To a solution of 13 parts of 17B-pyranyloxy-5a-androst-2-en-1-one in 200 parts of acetone is added a solution of 5 parts of p-toluenesulfonic acid monohydrate in 80 parts of methanol. The resultant mixture is heated at the boiling point under reflux for 15 minutes and thereupon allowed to stand at room temperatures for 48 hours. It is then poured into 5 volumes of water. The precipitate which forms is filtered 01f, washed with water, dried in air, and chrom-atographed on silica gel, using benzene-and ethyl acetate as developing solvents. From an eluate comprising 5% ethyl acetate in benzene, on evaporation of solvent and recrystallization of the residue from a mixture of acetone and hexane, 1718-hydroxy-5wandrOst-Z-en-1-one melting at 179181 is obtained. The product has the formula EXAMPLE 15 17/8-acetoxy-5a-andr0st-2-en-I-0ne.-Substitution of 2 parts of 17B-hydroxy-5a-andrQst-Z-en-l-one for the Setandrost-2-ene-la,l7fl-diol called for .in Example 11 atfords, by the procedure there detailed, 17fi-acet0xy-5ocandrost-Z-en-l-one, of the formula OOOOH:

EXAMPLE 16 (A) 1u-acctOxy-Ufl-pyranyl0xy-5a-andr0st-2-cne. A solution of 12 parts of 17,8-pyranylcxy-5a-androst-2-enld-Oi. in a mixture of 200 parts of pyridine and parts of acetic anhydride is allowed to stand at room temperatures for 48 hours. It is then poured into 3 volumes of cold water, whereupon the oily precipitate which forms is extracted into ether. The ether solution is consecutively washed with water, 5% hydrochloric acid, and aqueous 5% sodium bicarbonate, then dried over anhydrous potassium carbonate in the presence of decolorizing charcoal, filtered, and stripped of solvent by distillation. The residual oil is 1a-acetoxy-17,8-pyranyloxy-5aandrost-2-ene.

(B) Ia-acetOxy-Sa-androst-2-en-]7fi-0L-A solution of 12 parts of 1a-acetoxy-1718-pyranyloxy-5a-androst-2-ene and 7 parts of p-toluenesulfonic acid monohydrate in approximately 400 parts of methanol is allowed to stand at 30 for 1% hours. It is then poured into 3 volumes of water. The resultant mixture is extracted with ether. The ether extract is washed with water, dried over anhydrous potassium carbonate in the presence of decolorizing charcoal, and stripped of solvent by distillation. The residual dark yellow oil is the desired 1a-acetoxy-5ot-androst-2-en-17 8-ol, of the formula OH 3 l CH COQ I 1a-acetoxyJu-androst-Z-en-I7-one.-To a solution of 8 parts of la-acet Xy-Sa-andrOSt-Zen-17 3-01 in 120 parts of acetone is added a slight excess of-Jones reagent. The excess reagent is decomposed with 2-propanol, and the inorganic salts thrown down are thereupon removed by filtration. The filtrate is poured into 5 volumes of water. The mixture thus obtained is extracted with ether. The ether extract is washed with water, dried over anhydrous potassium carbonate in the presence of decolorizing charcoal, filtered, and stripped of solventby distillation. The residual yellow oil is chromatographed on silica gel, using benzene and ethyl acetate as developing solvents. From an eluate comprising 5% ethyl acetate in benzene, on distillation of solvent and recrystallization of the residue from acetone, there is obtained IOL-HJOCtOXY- 5u-androst-2-en-17-one melting at 170-173", and further characterized by a specific rotation of +3015 in chloroform solution at 28. The product has the formula C H 3 GHgCO? Q I/\ b,

EXAMPLE 18 1a-hydrOxy-Su-androst-Z-en-I7-0ne. Substitution of 20 parts of 1a-acetoxy-5a-androst-2-en-17-one for the 1a,17B-diacetoxy-17a-methyl-Su-androst-Z-ene called for in Example 4 aflords, by the procedures there detailed, 1a-hydroXy-Sa-androst-2-en-17-one, having the formula EXAMPLE 19 17u-ethynyZ-Sa-andrOst-Z-ene-Ia,]7/3-a'i0l.To 95 parts of diethyleneglycol dimethyl ether and 6 parts of diethyleneglycol monomethyl ether at 135 under nitrogen with vigorous agitation is added, portionwise, 25 parts of potassium hydroxide. Thereafter, temperature is maintained at 135 with vigorous agitation for /2 hour, whereupon the reactants are slowly cooled to room temperature and then to approximately 60, at which temperature acetylene is continuously introduced during 2 hours and While a solution of parts of Ia-aCCtOXY-Saandrost-2-en-17-one in approximately 14 parts of diethyleneglycol dimethyl ether is mixed in over a -minute period. 'Introduction of acetylene is continued for an hour longer, whereupon 60 parts of water is thoroughly mixed in. The resultant mixture is poured into 3 volumes of a mixture of ice and water incorporating approximately 48 parts of concentrated hydrochloric acid. The precipitate which forms is filtered off and taken up in ether. The ether solution is Washed with water, dried over anhydrous sodium sulfate in the presence of decolorizing charcoal, filtered, and stripped of solvent by distillation. The residual solid, recrystallized from aqueous methanol, afiords l7a-ethynyl 5a andrqst-2-ene-la,17,6- diol, which is characterized by peaks in the infrared spec- 10 trum of a chloroform solution at 2.75, 3.01, 3.4, and 6.01 microns. The product has the formula c5011 CH3 s on it What is claimed is: 1. A compound selected from the group consisting of compounds of the formula H3O H30 fl] and compounds of the formula wherein R is selected from the group consisting of hydrogen and lower ialkanoyl radicals; Z is selected from the group consisting of the carbonyl radical and radicals of the formula C-OR in which R is selected from the group consisting of hydrogen and ethynyl, methyl, and ethyl radicals and R is hydrogen; and the dotted line represents an optional double bond.

2. A compound of the formula wherein the dotted line in ring A represents an optional double bond.

3. 17a-methyl-5wandrost-2-ene-1a,17B-diol.

4. A compound of the formula CH CH3 wherein the dotted line in ring A represents an optional double bond.

1 1 5. 1v -acetoxy-17u-methyl-5a-androst-Z-en-1713-61. 6. A compound of the formula 3,257,428 12 7. 17B-acetoxy-5a-androst-2-en-I-one. 8. 17a-ethynyl-5a-androst-2-ene-1a,l7B-diol. 9. 17a-methyl-5wandrostane-10:,1713-di01.

5 References Cited by the Examiner UNITED STATES PATENTS 2,805,231 9/1957 Dodson etal 260--397.4 3,002,007 9/1961 Hoehm 260-3973 10 LEWIS GOTTS, Primary Examiner.

HENRY A. FRENCH, Assistant Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA 